Licochalcones B & D: Total syntheses and antiviral evaluation

Introduction: The number of cases of arboviruses transmitted by Aedes aegypt, such as Zika fever, Chikungunya fever and Mayaro virus disease has grown in recent years throughout the national territory due to climate changes that facilitated the proliferation of the vector. Currently, none of the three diseases mentioned has post-infection treatment. Seeking for alternatives against those neglected diseases, this research aims into the synthesis and evaluation of licochalcone B (LCB), licochalcone D (LCD) as agents against Zika Virus, Chikungunya Virus, and Mayaro Virus. LCB and LCD are natural retrochalcones with two phenyl rings connected by an α,β-unsaturated ketone, tri-hydroxylated at positions 3,4,4’ and methoxylated at position 2, differing only that LCD has an isoprenyl group at 3' position. The main substances are natural products (NPs) and were chosen as prototypes by the vast number of studies with flavonoids extracted from plants from Glycyrrhiza genus (as the licochalcones) as antivirals, antitumor, antioxidant, anti-inflammatory, antibacterial, etc. The NPs obtained from extraction are achieved with very low yields, resulting in a few micrograms of compounds from huge amounts of plants. For this reason, synthetic routes with high yields are needed to better explore these NPs, which also enable future structural changes seeking for better biological activity and lower toxicity. Method: The total syntheses of LCB and LCD will be performed by 5 to 7 steps synthetic routes. To obtain LCB, the starting materials 2,3,4-trihydroxybenzaldehyde and 4’-hydroxyacetophenone will be submitted to reactions of protection with bromomethyl methyl ether, O-methylation with iodomethane, Claisen-Schmidt condensation under basic catalysis and deprotection in acidic medium and methanol, and the route will be complemented with reactions of regioselective halogenation using N-iodosuccinimide/N-bromosuccinimide or I2 and Br2 and Suzuki-Miyaura coupling with palladium catalyst and boronic acid pinacol ester to obtain LCD. The reactions will be monitored by thin-layer chromatography and purified by crystallization, silica gel chromatography, reversed phase chromatography (C-18) and size exclusion chromatography (Sephadex® LH-20). The synthetized substances will be analyzed by 1H and 13C RMN and mass spectrometry for structural confirmation. After that, the compounds will be evaluated against Zika Virus, Mayaro Virus and Chikungunya Virus. Results: LCB was synthetized by a five-step synthesis with 12 % overall yield, while LCD is currently in development (the regioselective halogenation was performed with I2 with 90% (yield). LCB structure and all route intermediates were confirmed by 1H RMN, but further tests are needed to improve the overall yield. Antiviral assays were not performed yet.
Conclusion: The total synthesis of LCB was effectively performed by a five-step synthesis. LCD is currently being synthetized, and the halogenated-protected intermediate was usefully obtained.